The present invention relates to methods and apparatus for preparing liquid compounds for chemical and biological analysis, and more particularly, to equipment for dispensing minute volumes of liquid onto a substrate surface or well in an array in connection with drug discovery and diagnostic analysis.
As the field of biotechnology has developed, traditional techniques for analyzing chemical structures, such as the use of pipettes to manually deposit small amounts of liquid, have become impractical. Automated devices have been developed, for example, to permit parallel processing protocols for DNA diagnostics. Robotic devices with multiple pipettes have been used, but they are slow and consume unnecessarily large amounts of expensive chemical assays. In one form of such a device a matrix of individual pins is attached to a robotic arm. The spacing of the pins in sufficient to allow their terminal lower ends to be dipped into corresponding wells of a well plate, thereby wetting the end of each pin with the sample liquid. The robotic arm then moves the pin matrix to the surface of a target substrate and contacts the end of each pin with the surface. The target substrate surface can either be flat or configured to provide a plurality of liquid receiving vessels or wells which themselves may have minute amounts of other liquids already deposited into the same. Thus the transfer of minute amounts of liquid with so-called pin replicator or pin transfer devices can be wet-to-dry or wet-to-wet.
The continual contact of delicate pins to a substrate surface or well bottom leads to wear which can introduce errors. In addition, the substrate surface or well bottoms at either the pick-up end or the deposit end may not be truly co-planar therefore causing fluid transfer errors. In addition, the pins may not all be the same length due to tolerance variations. U.S. Pat. No. 6,024,925 assigned to Sequenom, Inc. of San Diego discloses an improved pin transfer assembly that uses individually spring biased hollow pins. However, the structure of the Sequenom pin transfer assembly is relatively complex, unduly expensive and subject to mechanical failures.
It is therefore the primary object of the present invention to provide an improved pin replicator or pin transfer assembly for dispensing minute volumes of liquid onto a substrate surface or wells in an array in connection with drug discovery, diagnostic analysis, and other applications.
In accordance with the present invention, several pin transfer assemblies are disclosed that utilize the surface tension of liquids for transferring minute quantities of liquid between two different locations, e.g. by picking up and dispensing minute volumes of liquid from wells in a first well plate to a flat substrate surface or into wells in a second well plate. The pin transfer assemblies can be used in connection with automated drug discovery, diagnostic analysis, and other applications. In a first embodiment the pin transfer assembly comprises a base plate, a plurality of pins reciprocable through corresponding holes in the base plate, and a free floating weight plate resting on top of the upper ends of the pins. The weight plate biases the pins toward their fully extended lowered positions but and accommodates a lack of co-planarity at either the pick up end or the receiving end of the liquid transfer process. A cover attaches to the base plate, encloses the pins and weight plate and guides the weight plate during vertical movement thereof In a second embodiment, the pins reciprocate through complementary arrays of holes in the base plate and an overlying spring plate biased apart by coil springs located around the periphery of the base plate. A foam layer sits on top of the spring plate and a weight plate sits on top of the foam plate. A single spring is positioned between a center of the weight plate and the cover to push the weight plate downwardly. The periphery of the cover guides the vertical movement of the weight plate and is connected to the periphery of the base plate. The periphery of the base plate is supported by a frame used to register the pin assembly in a receptacle of a manual or automated liquid transfer apparatus. The pins are biased to an intermediate position between their fully extended lowered positions and their fully retracted raised positions. The foam layer ensures that the pins can accommodate non-co-planarity at the pick up or receiving ends of the liquid transfer process. In a third embodiment, the spring plate, weight plate and coil springs are eliminated. A foam layer is positioned between the array of reciprocable pins and the cover for biasing the pin heads toward the base plate.